The present invention relates to certain substituted phenyl oxazolidinones and to processes for the synthesis of the same. This invention also relates to pharmaceutical compositions containing the compounds of the present invention as antimicrobials. The compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacterioides spp. and Clostridia spp. species, and acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
Increasing antibacterial resistance in Gram positive bacteria has presented a formidable treatment problem. The enterococci, although traditionally non virulent pathogens, have been shown, when associated with Vancomycin resistance, to have an attributable mortality of approximately 40%. Staphylococcus aureus, the traditional pathogen of post operative wounds, has been resistant to Penicillin due to production of penicillinases. This resistance was overcome by the development of various penicillinase stable xcex2 lactams. But the pathogen responded by synthesizing a modified target penicillin binding protein-2xe2x80x2 leading to less affinity for xcex2 lactam antibiotics and a phenotype known as Methicillin Resistant S. aureus (MRSA). These strains, till recently were susceptible to Vancomycin, which inspite of its various drawbacks, has become the drug of choice for MRSA infections. Streptococcus pneumoniae is a major pathogen causing pneumonia, sinusitis and meningitis. Until very recently it was highly susceptible to penicillin. Recently though, different PBP 2xe2x80x2 strains with different susceptibility to penicillin have been reported from across the globe.
Oxazolidinones are a new class of synthetic antimicrobial agents which kill gram positive pathogens by inhibiting a very early stage of protein synthesis. Oxazolidinones inhibit the formation of ribosomal initiation complex involving 30S and 50S ribosomes leading to prevention of initiation complex formation. Due to their novel mechanism of action, these compounds are active against pathogens resistant to other clinically useful antibiotics.
WO93/23384 application discloses phenyloxazolidinones containing a substituted diazine moiety and their uses as antimicrobials.
WO93/09103 application discloses substituted aryl and heteroaryl-phenyl-oxazolidinones useful as antibacterial agents
WO90/02744 application discloses 5-indolinyl-5xcex2-amidomethyloxazolidinones, 3-(fused ring substituted) phenyl-5xcex2-amidomethyloxazolidinones which are useful as antibacterial agents.
European Patent Publication 352,781 discloses phenyl and pyridyl substituted phenyl oxazolidinones.
European Patent Application 312,000 discloses phenylmethyl and pyridinylmethyl substituted phenyl oxazolidinones.
U.S. Pat. No. 5,254,577 discloses nitrogen heteroaromatic rings attached to phenyloxazolidinone.
U.S. Pat. Nos. 5,547,950 and 5,700,799 also disclose the phenyl piperazinyl oxazolidinones.
Other references disclosing various phenyloxazolidinones include U.S. Pat. Nos. 4,801,600 and 4,921,869; Gregory W. A., et al., J.Med.Chem., 32, 1673-81 (1989); Gregory W. A., et al., J.Med.Chem., 33, 2569-78 (1990); Wang C., et al., Tetrahedron, 45, 1323-26 (1989); Brittelli, et al., J.Med. Chem., 35, 1156 (1992); and Bio-organic and Medicinal Chemistry Letters, 9, pp. 2679-2684, 1999.
The objective of this invention is to synthesize, identify and profile oxazolidinone molecules which have good activity against multiply resistant gram positive pathogens like MRSA, VRE and PRSP. Some of these molecules have activity against MDR-TB and MAI strains, while others have significant activity against important anaerobic bacteria.
The compounds of the present invention are related by their substituted phenyloxazolidinone ring structure in the compounds disclosed to the publications described above except that the subject compounds have a diazine moiety attached to the phenyloxazolidinone which is further substituted by heterocyclic, aryl, substituted aryl, heteroaroamatic ring therefore the compounds are unique and have superior antibacterial activity.
Another object of the present invention is to provide processes for the novel phenyloxazolidinones derivatives that exhibit significantly greater antibacterial activity, than available with the present compounds against multiply resistant gram positive pathogens like MRSA, VRE and PRSP against MDR-TB and MAI strains, in order to provide safe and effective treatment of bacterial infections.
In order to achieve the above-mentioned objectives and in accordance with the purpose of the invention as embodied and broadly described herein, there is provided a process for the synthesis of novel phenyloxazolidinone derivatives represented by Formula I 
wherein
T is five to seven membered heterocyclic ring, aryl, substituted aryl, bound to the ring C with a linker w, preferred forms of T are selected from aryl and five membered heteroaryl which are further substituted by a group represented by R, wherein R is selected from the group consisting of xe2x80x94CN, COR5, COOR5, N(R6, R7), CON(R6, R7), CH2NO2, NO2, CH2R8, CHR9, xe2x80x94CHxe2x95x90Nxe2x80x94OR10, xe2x80x94Cxe2x95x90CHxe2x80x94R5, wherein R5 is selected from H, optionally substituted C1-C12, alkyl, C3-12, cycloalkyl, aryl, heteroaryl, R6 and R7, are independently selected from H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy; R8 and R9 are independently selected from H, C5-6 alkyl, F, Cl, Br, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR5, SR4, N(R6,R7) wherein R5 is selected from H, C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl substituted with one or more F, Cl, Br, I or OH and R6 and R7 are the same as defined earlier, R5 is selected from H, optionally substituted C5-12 alkyl, C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, aryl, heteroaryl, n is an integer in the range from 0 to 3;
X is CH, CHxe2x80x94S, CHxe2x80x94O and N;
Y and Z are independently selected from hydrogen, C1-6 alkyl, C3-12 and cycloalkyl C0-3 bridging groups;
U and V are independently selected from optionally substituted C1-6 alkyl, F, Cl, Br, C1-12 alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro;
W is selected from the group CH2, CO, CH2NH, xe2x80x94NHCH2, xe2x80x94CH2NHCH2, xe2x80x94CH2xe2x80x94N (R11)CH2xe2x80x94, CH2(R11)Nxe2x80x94, CH(R11), S, CH2( CO), NH wherein R11 is optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, aryl, heteroaryl; and,
R1 is selected from the group consisting of xe2x80x94NHC(xe2x95x90O)R2 wherein R2 is hydrogen, C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl substituted with one or more of F, Cl, Br, I or OH, N(R3, R4), xe2x80x94NR2C(xe2x95x90S)R3, xe2x80x94NR2C(xe2x95x90S)SR3 wherein R2 is the same as defined above, R3, R4 are independently selected from hydrogen, C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl substituted with one or more of F, Cl, Br, I or OH.
Preferred compounds of Formula I have R1 as acetamide and the most preferred compounds in this series would be prepared as the optically pure enantiomers having the (S)-configuration according to the Cahn-Ingold-Prelog notation at C5 of the oxazolidinone ring. The (S)-enantiomer of this series of compounds is preferred since it has two times more antibacterial activity than the corresponding racemic compound. The scope of the individual isomers and mixture of enantiomers of the structural Formula I are also covered in this invention.
Still more preferred compounds of the Formula I containing D ring as furanyl, thienyl and pyrrolyl ring systems and further substituted by substitutions Q and P is represented by Formula II 
wherein
U and V are independently selected from optionally substituted C1-6 alkyl, F, Cl, Br, C1-12 alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro;
X is CH, CHxe2x80x94S, CHxe2x80x94O and N;
Y and Z are independently selected from hydrogen, C1-6 alkyl, C3-12 and cycloalkyl C0-3 bridging groups; and,
W is selected from the group CH2, CO, CH2NH, xe2x80x94NHCH2, xe2x80x94CH2NHCH2, xe2x80x94CH2xe2x80x94N (R11)CH2xe2x80x94, CH2(R11)Nxe2x80x94, CH(R11), S, CH2(CO), NH wherein R11 is optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, aryl, heteroaryl.
Preferred compounds of Formula II of this invention are those when Q and P are independently selected from the group consisting of xe2x80x94CN, COR5, COOR5, N (R6, R7), CON(R6,R7), CH2NO2, NO2, CH2R8, CHR9, xe2x80x94CHxe2x95x90Nxe2x80x94OR10, Cxe2x95x90CHxe2x80x94R5, wherein R5 selected from the group consisting of H, optionally substituted C1-12alkyl, C3-12 cycloalkyl, aryl, or heteroaryl; R6, R7 are independently selected from H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, R8, R9 and are independently selected from the group consisting of H, C1-6 alkyl, F, Cl, Br, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR4, SR4,N(R6, R7), R10xe2x95x90H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, aryl, heteroaryl except Wxe2x95x90(CO), Q and Pxe2x95x90H.
In the more preferred compounds represented by Formula II ring C may be 6-8 membered in size and the larger rings may have either two or three carbons between each nitrogen atom, for example: 
The ring C may be bridged to form a bicyclic system as shown below: 
When ring C is optionally substituted at positions Y and Z with alkyl groups, cycloalkyl groups, fluoro group, carboxylic and corresponding esters, amides, substituted alkyls or bridging alkyl groups are as shown below: 
When ring C is 6 membered in size and X is xe2x80x94CHxe2x80x94(NHR), the following rings are preferred ones wherein R11 is the same as defined earlier. 
In addition to the above, ring C also includes the following structures: 
Still more preferred compounds of Formula II when M=Sulphur is represented by Formula III 
wherein
U and V are independently selected from optionally substituted C1-6 alkyl, F, Cl, Br, C1-12 alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro;
X is CH, CHxe2x80x94S, CHxe2x80x94O and N;
Y and Z are independently selected from hydrogen, C1-6 alkyl, C3-12 and cycloalkyl C0-3 bridging groups;
W is selected from the group CH2, CO, CH2NH, xe2x80x94NHCH2, xe2x80x94CH2NHCH2, xe2x80x94CH2xe2x80x94N (R11)CH2xe2x80x94, CH2(R11)Nxe2x80x94, CH(R11), S, CH2(CO), NH wherein R11 is optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, aryl, heteroaryl; and,
Q and P are independently selected from the group consisting of xe2x80x94CN, COR5, COOR5, N(R6, R7), CON(R6,R7), CH2NO2, NO2, CH2R8, CHR9, xe2x80x94CHxe2x95x90Nxe2x80x94OR10, Cxe2x95x90CHxe2x80x94R5, wherein R5 is selected from the group consisting of H, optionally substituted C1-12alkyl, C3-12 cycloalkyl, aryl, or heteroaryl; R6, R7 are independently selected from H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, R8, R9 and are independently selected from the group consisting of H, C1-6 alkyl, F, Cl, Br, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR4, SR4,N(R6, R7), R10xe2x95x90H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, aryl, heteroaryl except Wxe2x95x90(CO), Q and Pxe2x95x90H.
More preferred Q, P substitutions are nitro, aldehydes and halides.
Preferably W is selected from the groups consisting of CH2, C(xe2x95x90O), C(xe2x95x90O)xe2x80x94C(xe2x95x90O), CH2NH, xe2x80x94NHCH2, xe2x80x94CH2NHCH2, xe2x80x94CH2xe2x80x94N(CH3)CH2xe2x80x94, CH2(CH3)Nxe2x80x94, CH(CH3), S and CH2(Cxe2x95x90O), xe2x80x94NH. The most preferred compounds of Formula III are as follows:
xe2x80x94(S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-2-thienyl(5-nitro)methyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
xe2x80x94(S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-(2-thienyl)dicarbonyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
xe2x80x94(S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(5-nitro-2-thienoyl)]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride
Still more preferred compounds of Formula II is represented by Formula IV 
containing oxygen atom in ring D of Formula II, wherein
U and V are independently selected from optionally substituted C1-6 alkyl, F, Cl, Br, C1-12 alkyl substituted with one or more of F, Cl, Br, I, preferably U and V are hydrogen or fluoro;
X is CH, CHxe2x80x94S, CHxe2x80x94O and N;
Y and Z are independently selected from hydrogen, C1-6 alkyl, C3-12 and cycloalkyl C0-3 bridging groups;
W is selected from the group CH2, CO, CH2NH, xe2x80x94NHCH2, xe2x80x94CH2NHCH2, xe2x80x94CH2xe2x80x94N (R11)CH2xe2x80x94, CH2(R11)Nxe2x80x94, CH(R11), S, CH2(CO), NH wherein R11 is optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, aryl, heteroaryl; and,
Q and P are independently selected from the group consisting of xe2x80x94CN, COR5, COOR5, N(R6,R7), CON(R6,R7), CH2NO2, NO2, CH2R8, CHR9, xe2x80x94CHxe2x95x90Nxe2x80x94OR10, Cxe2x95x90CHxe2x80x94R5, wherein R5 is selected from the group consisting of H, optionally substituted C1-12alkyl, C3-12 cycloalkyl, aryl, or heteroaryl; R6, R7 are independently selected from H, optionally substituted C1-12 alkyl, C3-12 cycloalkyl, C1-6 alkoxy, R8, R9 and are independently selected from the group consisting of H, C1-6 alkyl, F, Cl, Br, C1-12 alkyl substituted with one or more of F, Cl, Br, I, OR4, SR4,N(R6, R7), R10xe2x95x90H, optionally substituted C1-12 alkyl C3-12 cycloalkyl, C1-6 alkoxy, C1-6 alkyl, aryl, heteroaryl except Wxe2x95x90(CO), Q and Pxe2x95x90H.
More preferred Q and P substitutions are nitro, aldehydes and halides.
Preferably W is selected from the groups consisting of CH2, C(xe2x95x90O), C(xe2x95x90O)xe2x80x94C(xe2x95x90O), CH2NH, xe2x80x94NHCH2,xe2x80x94CH2NHCH2, xe2x80x94CH2xe2x80x94N(CH3)CH2xe2x80x94, CH2(CH3)Nxe2x80x94, CH(CH3), S, CH2(Cxe2x95x90O), and xe2x80x94NH.
The most preferred compounds of Formula IV are as follows:
xe2x80x94(S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-(5-nitro-2-furoyl)piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
xe2x80x94(S)xe2x80x94N-[[3-[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
xe2x80x94(S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-(5-nitro-2-furoyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide.
xe2x80x94(S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-2-furyl(5-nitro)methyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide.
The compounds of the present invention are useful as antimicrobial agents, effective against a number of human and veterinary pathogens, particularly aerobic Gram-positive bacteria, including multiply-antibiotic resistant staphylococci and streptococci, as well as anaerobic organisms such as Mycobacterium tuberculosis and other mycobacterium species.
For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, suppositories, and ointments. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, or tablets disintegrating agents; it can also be as finely divided solid which is in admixture with the finely divided active compound. For the preparation of tablets, the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 5 to about 70 percent of the active ingredient. Suitable solid carriers are lactose, pectin, dextrin, starch, gelatin, tragacanth, low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it. Similarly, capsules can be used as solid dosage forms suitable for oral administration.
Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection. Such solutions are prepared so as to be acceptable to biological systems (isotonicity, pH, etc.). Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing, and thickening agents as desired. Aqueous suspension suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.
Ointment preparations contain heavy metal salts of a compound of Formula I with a physiologically acceptable carrier. The carrier is desirably a conventional water-dispersible hydrophilic or oil-in-water carrier, particularly a conventional semi-soft or cream-like water-dispersible or water soluble, oil-in-water emulsion infected surface with a minimum of discomfort. Suitable compositions may be prepared by merely incorporating or homogeneously admixing finely divided compounds with the hydrophilic carrier or base or ointment.
Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete capsules, powders in vials or ampoules, and ointments capsule, cachet, tablet, gel, or cream itself or it can be the appropriate number of any of these packaged forms.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from less than 1 mg to 100 mg according to the particular application and the potency of the active ingredient.
In therapeutic use as agents for treating bacterial infections the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 3 mg to about 40 mg per kilogram daily. The dosages, however, may be varied depending upon the requirements of the patient and the compound being employed. Determination of the proper dosage for a particular situation is within the smaller dosages which are less than the optimum dose. Small increments until the optimum effect under the daily dosage may be divided and administered in portions during the day if desired.
In order to achieve the above mentioned objects in accordance with the purpose of the invention as embodied and broadly described herein, there are provided process for the synthesis of compounds of Formulae I, II, III and IV. Pharmaceutically acceptable non-toxic acid addition salts of the compounds of the present invention of Formulae I, II, III and IV may be formed with inorganic or organic acids, by methods well known in the art.
The present invention also includes within its scope prodrugs of the compounds of Formulae I, II, III and IV. In general, such prodrugs will be functional derivatives of these compounds which readily get converted in vivo into defined compounds. Conventional procedures for the selection and preparation of suitable prodrugs are known.
The invention also includes pharmaceutically acceptable salts, the enantiomers, diastereomers, N-oxides, prodrugs, metabolites in combination with pharmaceutically acceptable carrier and optionally included excipient.
Other objects and advantages of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learned by the practice of the invention. The objects and the advantages of the invention may be released and obtained by means of the mechanism and combination pointed out in the appended claims.
The compounds of the present invention may be prepared by following the reaction sequences as depicted in the schemes defined below.
Mainly five different amines of Formula V 
identified as five different cores, namely
xe2x80x94(S)xe2x80x94N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (core I);
xe2x80x94(S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-methyl]amino]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (core II);
xe2x80x94(S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-methyl]amino methyl]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (core III);
xe2x80x94(S)xe2x80x94N-[[3-[4-[4-N-methylamino piperidin-1-yl]-3-fluorophenyl}-2-oxo-oxazolidin-5-yl]methyl acetamide (core IV); and,
xe2x80x94(S)xe2x80x94N-[[3-[3 [Fluoro-4-(N-1-homopiperazinyl)phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide (core V),
were used for analoguing purposes.
Key intermediate amines of Formula V for the analogue preparation were prepared from commercially available reagents wherein G in amines of Formula V is defined as NH, CH(NHR), xe2x80x94CHxe2x80x94CH2NHR wherein R is H, ethyl, methyl, isopropyl, acetyl, cyclopropyl, alkoxy, or acetyl and U, V, Y and Z are as defined for Formula II. Some amines of Formula V are already known in the literature and are given by reference and if they have been made for the first time or by a different procedures or variation of known procedure they are described in detail in the experimental section.
Optically pure amines of Formula V could be obtained either by one of a number of asymetric syntheses or alternatively by resolution from a racemic mixture by selective crystallization of a salt prepared, with an appropriate optically active acid such as dibenzoyl tartrate or 10-camphorsulfonic acid, followed by treatment with base to afford the optically pure amine.
The compounds of the present invention represented by general Formula I may be prepared by the method of reaction in Scheme I: 
In Scheme I, the heteroaromatic group with the corresponding appendage can be introduced on the nitrogen atom of ring C of compounds of Formula V by one of the methods described below to given Formula I, wherein R12 is a suitable leaving group well known to one of ordinary skill in the art such as fluoro, chloro, bromo, SCH3, xe2x80x94SO2CH3, xe2x80x94SO2CF3 or OC6H5 etc. and G in amines of Formula V is defined as NH, CH(NHR13), xe2x80x94CHxe2x80x94CH2NHR13 wherein R13 is H, ethyl, methyl, isopropyl,acetyl, cyclopropyl, alkoxy or acetyl U, V, Y and Z are as defined for Formula I earlier.
Amine of structure of Formula V is reacted with a heteroaromatic compound of Formula R-T-W-R12 wherein R, T, W are the same as defined for Formula I earlier. For the preparation of compounds of Formula I when W is equal to CH2 corresponding aldehyde can be used through a process of reductive amination and is attached to amine of Formula V.
Similarly, for the preparation of compound of Formula I wherein W is equal to Cxe2x95x90O corresponding acid can be used and the amino of Formula V can be acylated through activated esters in the presence of condensing agents such as 1,3-dicyclohexylcarbodiimide (DCC) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC). Other methods of acylation can also be employed.
Alternatively, the compounds having carbonyl link can also be made by reacting heteroaromatic compound of the Formula VI 
such as N-methyl pyrrole with the intermediate amine of Formula V in the presence of triphosgene or phosgene. Carbonyl linkers may also be introduced between hetero-aromatic compound such as 3-bromothiophene and amine of Formula V with carbon monoxide and the catalyst such as Pd (PPh3)2Cl2. Extended chain pyrroles having dicarbonyl linkers can also be obtained from treatment with oxalyl chloride and amine of the Formula V.
The reduction of the carbonyl linkers using the standard reducing agents results in the formation of methylene linkers.
Preparation of the compound of Formula I as represented by Formula II (where heterocycle is 5 membered ring) is accomplished as exemplified below by three methods A, B and C as shown in Scheme II: 
Method A
Amine of structure V is reacted with a heteroaromatic compound of Formula VI having R12 as a suitable leaving group defined earlier for Scheme I. Q, P and M are as defined for Formula II.
The reaction is done in a suitable solvent such as dimethylformamide, dimethylacetamide, ethanol or ethylene glycol at a suitable temperature in the range of xe2x88x9270xc2x0 C. to 180xc2x0 C. to afford compounds of Formula I. The presence of a suitable base such as triethylamine, diisopropyl amine, potassium carbonate, sodium bicarbonate is useful in some cases to improve the yield of the reaction.
Method B
Reductive alkylation of the amine intermediate of Formula V, with the corresponding heterocyclic aldehydes of the Formula VI, such as furaldehyde (Q, Pxe2x95x90H, Mxe2x95x90O; R12 is CHO) using known reducing agents well known to one of ordinary skill in the art such as sodium triacetoxyborohydride or sodium cyanoborohydride gave the products of Formula II wherein Wxe2x95x90CH2 as shown in the Scheme II.
Method C
Acylation of intermediate amines of Formula V with heterocyclic acid of Formula VI, such as 2-furoic acid (Q,Pxe2x95x90H; Mxe2x95x90O, R12xe2x95x90COOH) gave products of Formula II, wherein Wxe2x95x90CO, as shown in the Scheme II wherein U, V, Y, Z, X, W, M, P, Q and R12 are the same.
xe2x80x94(S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(5-nitro-2-thienoyl)]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride was prepared using this method.
Alternatively, the compounds having carbonyl link can also be made by reacting heteroaromatic compound of the Formula VI such as N-methyl pyrrole with the intermediate amine of Formula V in the presence of triphosgene or phosgene. Carbonyl linkers may also be introduced between heteroaromatic compound such as 3-bromothiophene and amine of Formula V with carbon monoxide and the catalyst such as Pd (PPh3)2Cl2. Extended chain pyrroles having dicarbonyl linkers can also be obtained from treatment with oxalyl chloride and amine of the Formula V.
The reduction of the carbonyl linkers using the standard reducing agents results in the formation of methylene linkers. 
The compounds prepared by Scheme I represented by Formula VII 
were further used as starting compounds for further derivatisation as represented by Scheme III wherein U, V, Y, Z, X, W, P, Q, n and M are the same as defined earlier. The group R14 was transformed in one to five steps into final compounds of Formula VIII 
wherein U, V, Y, Z, n, X, W, P and M are the same as defined earlier containing transformed group R15. In most cases the R14 group in starting compounds were compounds containing R14 as aldehyde and ketones.
The following compounds are exemplified in Scheme-IIIA, IIIB and IIIC. 
(S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1{2-furyl-[4-(5-hydroxymethyl)methyl}]piperazinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide represented by Formula X was prepared by reducing aldehyde of Formula IX with sodium borohydride.
(S)xe2x80x94N-[[3-[3-fluoro-4-[N-1{2-furyl-[4-(5-fluoromethyl)methyl}]piperazinyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide of Formula XI (R161=CH2F) was prepared by reacting (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1{2-furyl-[4-(5-hydroxymethyl)methyl}]piperazinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide by reacting Formula X with diethylamino sulfurtrifluoride.
(S)xe2x80x94N-[[3-[3-fluoro-4-[N-1{2-furyl-[4-(5-difluoromethyl)methyl}]piperazinyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide of Formula XI (R16xe2x95x90CH2F2) was prepared by reacting (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-furyl(5-formyl)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula IX with diethylamino sulfurtrifluoride as shown in Scheme IIIA. 
(S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-furyl(5-formyl)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula IX was reacted with hydroxylamine and hydrazine hydrate to give (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1-[4-(2-furyl-(5-aldoxime)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XII 
and (S)xe2x80x94N-[[3-[3-Fluoro-4[N-1-[4-{2-furyl-(5-hydrazone)-methyl}]-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide of Formula XII 
(S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1[4-{2-furyl(5-aldoxime(methyl-4-(N-carboxyaminophenyl acetate)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide of Formula XII 
was made starting from (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1-[4-(2-furyl-(5-aldoxime)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XII 
and reacting with isocyanate.
(S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1[4-{2-furyl(5-cyano)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XII (R17xe2x95x90CN) was prepared from (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1[4-{2-furyl(5-aldoxime)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XII 
by the use of trifilic anhydride and triethylamine.
(S)xe2x80x94N-[[3-Fluoro-4-[N-1[5-(1,3-dioxane)-2-furylmethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XII 
was made using (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-furyl(5-formyl)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula IX with 1,3-propane diol and BF3 etherate. 
(S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-furyl(5-carboxy)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XIII was made using (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-furyl(5-formyl)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide of Formula IX by oxidation with Ag2O.
[[3-Fluoro-4-[N-1[5-(formamido)-2-furylmethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XIV 
was made by reacting (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-(2-furyl-(5-carboxyethyl)methyl)piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide with aqueous ammonia.
(S)xe2x80x94N-[[3-Fluoro-4-[N-1[5-(4-(tert butoxy carbonyl)amino piperidine)-2-furylmethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XIV 
was made by reacting (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-(2-furyl-(5-carboxy)methyl)piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XIII with thionyl chloride and 4-(tert butoxy carbonyl)amino piperidine.
(S)xe2x80x94N-[[3-Fluoro-4-[N-1[5-(morpholine-1-carbonyl)-2-furylmethyl]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XIV 
was made by reacting (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-(2-furyl-(5-carboxy)methyl)-piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of Formula XIII with morpholine in the presence of oxalyl chloride.
The transformations effected are described in the experimental section. In the above synthetic methods where specific acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. are mentioned, it is to be understood that the other acids, bases, solvents, catalysts, oxidising agents, reducing agents etc. may be used. Similarly, the reduction temperature and duration of the reaction may be adjusted according to the need. An illustrative list of particular compounds according to the invention and capable of being produced by the above mentioned schemes include:
Compound No. Chemical Name
1. (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1-[4-(2-furoyl) piperazinyl]]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
2. (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1[4-{2-furyl(5-formyl)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
3. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-(2-furyl-(5-carboxyethyl)methyl)piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
4. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-(5-bromo-2-furoyl)]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
5. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-(5-chloromethyl-2-furoyl)piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
6. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-(5-nitro-2-furoyl)piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
7. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-(2-thienyl)dicarbonyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
8. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(3-furoyl)]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]-methyl]acetamide
9. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-furyl(5-bromo)methyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
10. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-thienyl(5-chloro)methyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
11. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(2-furylmethyl)]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
12. (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1[4-(2-thienylmethyl)]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
13. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(2-thienylacetyl)]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
14. (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1[4-{2-thienyl(4-bromo)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
15. (S)xe2x80x94N-[[3-[3-fluoro-4-[N-1-[4-{2-furyl-(5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
16. Hydrochloric salt of (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-furyl(5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
17. Citrate slat of (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-furyl(5-nitro)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
18. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(2-pyrrolylmethyl)]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
19. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-thienyl(3-methyl)methyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
20. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(3-furylmethyl)]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
21. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-thienyl(5-methyl)methyl}]piperazinyl]phenyl]2oxo-5-oxazolidinyl]methyl]acetamide
22. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-pyrrole(1-methyl)methyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
23. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-thienyl(5-nitro)methyl}]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
24. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-[2-furyl {5-(N-thiomorpholinyl)methyl}methyl]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
25. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-[2-furyl{5-(N-morpholinyl)methyl}methyl]]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
26. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-furyl(5-acetoxymethyl)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
27. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-thienyl(5-bromo)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
28. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-(5-nitro-2-furylmethyl)piperazinyl]phenyl]-2-oxo-oxazolidinyl]methyl]dichloroacetamide
29. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(5-nitro-2-thienoyl)]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride
30. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(2xe2x80x2,2xe2x80x2-diphenyl-2xe2x80x2-hydroxyacetyl)]piperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
31. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-nitro-2-furoyl)-N-methyl]amino]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
32. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(3-furoyl)-N-methyl]amino]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
33. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-bromo-2-furoyl)-N-methyl]amino]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
34. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-nitro-2-thienylmethyl)-N-methyl]-amino]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
35. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-nitro-2-furylmethyl)-N-methyl]amino]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
36. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-formyl-2-furylmethyl)-N-methyl]amino-methyl]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
37. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-carboxyethyl-2-furylmethyl)-N-methyl]aminomethyl]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
38. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(2-thiopheneacetyl)-N-methyl]amino-methyl]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
39. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-nitro-2-thienylmethyl)-N-methyl]-amino-methyl]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
40. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-nitro-2-furylmethyl)-N-methyl]amino-methyl]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
41. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-2furyl(5formyl)methylaminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
42. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-(3,5-difluorobenzoyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
43. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-(5-bromo-2-furoyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
44. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-(5-nitro-2-furoyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
45. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-3-furoyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
46. (S)xe2x80x94N-{3-[4-[4-(N-methyl, N-2-furoyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl methyl]acetamide
47. (S)xe2x80x94N-{3-[4-[4-(N-methyl,2-thiopheneacetyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo oxazolidin-5-yl methyl]acetamide
48. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-2furylmethyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
49. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-3-furyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
50. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-2-furyl(5-nitro)methyl)aminopiperidine-1-yl]-3-fluorphenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
51. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-2-thienyl(5-nitro)methyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
52. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-2-thienylmethyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
53. (S)xe2x80x94N-[[3-[4-[4-(N-methyl-N-(5-methyl-2-thienylmethyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl]methyl]acetamide
54. (S)xe2x80x94N-{3-[4-[4-(N-methyl,2-(5-bromo)thienylmethyl)aminopiperidine-1-yl]-3-fluorophenyl]-2-oxo-oxazolidin-5-yl methyl]acetamide
55. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-furyl(5-formyl)methyl}]homopiperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
56. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(2-thienylacetyl)]homopiperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
57. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-{2-thienyl(5-nitro)methyl}]homopiperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
58. (S)xe2x80x94N[[3-[3-Fluoro-4-[N-1[4-(3-furylmethyl)]homopiperazinyl]phenyl]2-oxo-5-oxazolidinyl]methyl]acetamide
59. (S)xe2x80x94N-[[3-[3-fluoro-4-[N-1{2-furyl-[4-(5-difluoromethyl)methyl}]piperazinyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide
60. (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1-[4-(2-furyl-(5-aldoxime)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
61. (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1[4-{2-furyl(5-aldoxime(methyl-4-(N-carboxyaminophenylacetate)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
62. (S)xe2x80x94N-[[3-[3-Fluoro-4[N-1-[4-{2-furyl-(5-hydrazone)-methyl}]-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]-methyl]acetamide
63. (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1{2-furyl-[4-(5-hydroxymethyl)methyl}]piperazinyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
64. (S)xe2x80x94N-[[3-[3-Fluoro-4-[N-1[4-{2-furyl(5-cyano)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
65. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{2-furyl(5-carboxy)methyl}]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
66. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[5-(1,3-dioxane)-2-furylmethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
67. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[5-(formamido)-2-furylmethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
68. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[5-(morpholine-1-carbonyl)-2-furylmethyl]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
69. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[5-(4-(tert butoxy carbonyl)amino piperidine)-2-furylmethyl]piperazinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
70. (S)xe2x80x94N-[[3-Fluoro-4-[N-1[4-{(Z)-2-methoxyimino-2-(2-furyl)acetyl}]piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
71. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(2-thiopheneacetyl)-N-methyl]amino]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
72. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-formyl-2-furylmethyl)-N-methyl]-amino]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
73. (S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1a)-6-[N-(3-thienoyl)-N-methyl]amino]-3-azabicyclo[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
74. (S)xe2x80x94N-[[3-[3-fluoro-4-[N-1{2-furyl-[4-(5-fluoromethyl)methyl}]piperazinyl]-2oxo-5-oxazolidinyl]-methyl]acetamide
Pharmacological Testing
The compounds of the invention display antibacterial activity when tested by the agar incorporation method. The following minimum inhibitory concentrations (xcexcg/ml) were obtained for representative compounds of the invention which are given below in the following tables.
Guide to Table Abbreviations
1) S. aureus ATCC 25923xe2x80x94Staphylococus aureus ATCC 25923
2) MRSA 15187xe2x80x94Methicillin Resistant Staphylococcus aureus 
3) Ent. faecalis ATCC 29212xe2x80x94Enterococcus faecalis ATCC 29212
4) Ent. faecium 6Axe2x80x94Enterococcus faecium 6A Van(copyright), Cipro(copyright)
5) Strep. pne. ATCC 6303xe2x80x94Streptococcus pneumoniae ATCC 6303
6) Strep. pyog. ATCC 19615xe2x80x94Streptococcus pyogenes 
7) S. epidermidisxe2x80x94Staphylococcus epidermidis ATCC 12228
The in vitro antibacterial activity of the compounds were demonstrated by the agar incorporation method (NCCLS M 7 and M 100-S8 documents). Briefly, the compounds were dissolved in DMSO and doubling dilution of the compounds were incorporated into Meuller Hilton agar before solidification. Inoculum was prepared by suspending 4 to 5 colonies into 5 ml of normal saline solution and adjusting the turbility to 0.5 Macfarland turbidity standard tables (1.5xc3x97108 CFU/ml), after appropriate dilutions, 104 CFU/spot was transfered into the surface of dried plate and incubated for 18 hours (24 hours for MRSN studies). The concentration showing no growth of the inoculated culture was recorded as the MIC. Appropriate ATCC standard strains were simultaneously tested and result recorded only when the MIC""s against standard antibiotics were within the acceptable range.
The compounds of the present invention represented by general Formula I may be prepared by the method of reaction in Scheme I. Key intermediate amines of Formula V for the analogue preparation were prepared by the synthetic procedures described below from commercially available reagents. The compounds of Formula I were made by either Method A, B, or C.
Amines already known in the literature are given by reference and if they have been made by a different procedures they are described in detail.
Mainly five different amines of Formula V identified as five different cores namely
(S)xe2x80x94N-[[3-[3-Fluoro-4-(N-piperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (core I),
(S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-methyl]amino]-3-azabicyclo-[3.1.0]hexane]benzyl]-2-oxo-5-oxazolidinyl]methyl] acetamide (core II),
(S)xe2x80x94N-[[3-[3-Fluoro[4-[3-(1xcex1,5xcex1,6xcex1)-6-[N-(5-nitro-2-furylmethyl)-N-methyl]amino]-3-azabicyclo-[3.1.0]hexane]phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (core III),
(S)xe2x80x94N-{3-[4-[4-N-methylaminopeperidin-1-yl]-3-fluorophenyl}-2-oxo-oxazolidin-5-yl]methyl acetamide (core IV), and
(S)xe2x80x94N-[[3-[3[Fluoro-4-N-1-homopiperazinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (core V)
are shown in the examples given below.
Most of the compounds were characterized using NMR, IR and were purified by chromatography. Crude products were subjected to column chromatographic purification using silica gel (100-200 or 60-120 mesh) as stationery phase.
The examples mentioned below demonstrate the general synthetic procedure as well as the specific preparation for the preparation for the preferred compound. The examples are given to illustrate the details of the invention and should not be constrained to limit the scope of the present invention.